Innate immunity is the first line of defense designed to protect the host from invading pathogens, including HIV. We have previously demonstrated that natural killer (NK) cell- mediated suppression can be potent and that it is related to the stage of HIV infection as well as the level of HIV plasma viremia. Our study revealed that HIV viremia impairs the ability of NK cells to secrete CC-chemokines and alters the expression of various inhibitory and chemokine receptors expressed on NK cells. Further analysis of NK-cell specific surface receptors revealed upregulation of inhibitory NK receptors and chemokine receptor CCR5. In addition, our data showed CCR5 upregulation to be induced as a result of immune activation while induction of iNKRs appeared to be a direct result of an HIV-induced effect. Analysis of NK cell interactions with R5 and X4 HIV envelopes showed profound suppression of generic NK cell function upon exposure to these envelopes. DNA microarray analyses of NK cells from HIV viremic patients showed upregulation of genes induced by interferon. Further studies will address the HIV-NK cell interactions and explore the cellular and molecular basis for this suppressive effect.